An outbreak of histoplasmosis estimated to involve more than 100 000 residents in Indianapolis, Indiana, occurred between September 1978 and August 1979. In the 435 cases evaluated, 52% of the patients were between 15 and 34 years old, and 63% were black. Fifteen patients died, and 46 had progressive disseminated infection. Twenty-four patients had pericarditis, and 26 had rheumatologic syndromes. Unusual manifestations that occurred in 18 patients included esophageal and vocal cord ulcers, parotitis, adrenal insufficiency, uveitis, fibrosing mediastinitis, interstitial nephritis, intestinal lymphangiectasia, and epididymitis. The highest attack rate was in the central part of the city, which is a densely populated, disproportionately black section. The source of the outbreak has not been proved by positive culture results; two sites, however, were suspected on an epidemiologic basis.